Project Summary Despite a high rate of screening resulting in early identification of most of the 220,800 new cases of prostate cancer in the USA, there are still about 28,000 deaths, due to development of metastatic and treatment resistant disease. The blood samples collected on 632 unique patients out of 790 patients in the phase 3 trial, E3805: Chemohormonal versus Androgen Ablation Therapy for Extensive Disease (CHAARTED) in prostate cancer offers a very unique and expeditious opportunity to study blood borne biomarkers and related biological processes associated with a good versus poor response to testosterone suppression - the backbone of therapy for metastatic prostate cancer. This 3-year R01 application focuses on assessing blood borne proteins and androgens related to distinct biological processes purported to be associated with resistance to androgen deprivation therapy (ADT). The biological processes to be addressed include (i) bone biology (ii) androgens; (iii) inflammation and (4) metabolism. Each of these processes has preclinical and epidemiological data that support the hypothesis that one or more of them may be associated with a poor response to ADT. Although, there is substantial data in the CRPC setting, there is either no data or only scant data in the metastatic hormone sensitive setting. The samples from the E3805: CHAARTED trial provides the opportunity for the first time to prospectively assess whether one or more of these biological processes can identify patients at early time-points who are destined to have a poor response to ADT. In turn, these biological processes could possibly be credential as targets to abrogate and improve the efficacy of ADT. We will use a mutilplex ELISA assay to efficiently study 30 proteins using 1 mL of serum from each patient: bone alkaline phosphatase, osteocalcin, osteopontin, osteonectin, sclerostin, osteoprotegrin, RANK ligand, CRP, TGF?1, 2 and 3, IL-8, TNF-?, IL-6, IL1-?, IL-1?, IL-10, MIP-1?, MIP-1?, MIP-3?, SDF-1, MCP-1, MCP-2, Leptin, Adiponectin, IGF-1, IGF-1R, IGFBP-1, IGFBP-3, and IGFBP-4. A mass spectrometry approach will be used to measure a panel of androgens. pregnenolone, progesterone, testosterone and androstenedione (AED), dihydrotestosterone (DHT) and dehydro-epiandrosterone (DHEA) and DHEA-Sulfate. Samples have been obtained from baseline, 6 months after randomization and at progression. This will allow assessments of absolute levels at each time as prognostic markers of response to ADT but also allow assessment of changes over time. The latter will allow an assessment of biological processes that emerge and may be associated with development of castration resistance. Finally, by assessing the samples from patients who received early docetaxel we can assess for possible biomarkers predictive of early benefit from early docetaxel ? the major finding of the E3805 CHAARTED trial. This may allow accurate patient selection and spare patients who did not benefit from early docetaxel the side effects of this chemotherapeutic.